TWI542344B - Sodium ibuprofen tablets and methods of manufacturing pharmaceutical compositions including sodium ibuprofen - Google Patents

Description

Sodium ibuprofen ingot and method for preparing pharmaceutical composition comprising sodium ibuprofen

The present invention relates to a novel ibuprofen sodium core and coated lozenge/capsule composition having a lower sodium content than other commercially available sodium ibuprofen dosage forms, and A method of sodium ibuprofen core and a corresponding pharmaceutically acceptable composition. The advantage of the sodium ibuprofen core and the coated core sodium ibuprofen composition and formulation is that the tablet/capsule core formed thereof has a maximum daily sodium content of less than 140 mg/day for the patient (based on The tablet/capsule composition is calculated), and further provides an ibuprofen sodium/capsule core and a corresponding coated ibuprofen sodium core, which exhibit improved physical stability, high lozenge/ Capsule hardness and high ibuprofen sodium core strength, added and balanced excellent solubility and bioavailability characteristics. A further advantage of the pharmaceutically acceptable sodium ibuprofen core and coating core composition, formulation, and method of making the same is that it can be produced in large quantities without the presence of unacceptable amounts of undesirable tablets.

Solid dosage forms of ibuprofen are well known. Although the ibuprofen tablet compositions are commercially available, poor tablet compression, stability and disintegration remain critical formulation issues. While tablets which are typically compressed under low compression forces dissolve faster than tablets formed at high compression forces, tablets produced at lower pressures typically have a high degree of brittleness. International Patent Publication No. WO 2004/035024 A1 is a formulation of sodium ibuprofen A typical example. However, the tablet has only sufficient, but not optimal hardness, and its high total sodium content is unfavorable to the patient, especially for those who are directly attained by the pharmacy and the daily users. In addition, prior to administration, the comminution and rupture of the tablet may result in a dose of the active ingredient per tablet that is not necessarily the core of the defect, including chipping and sticking. In addition, high brittleness can also cause the tablet to rupture, resulting in waste during factory processing.

The present invention addresses these and other problems associated with the prior art. The present invention provides an improved sodium ibuprofen core having a lower sodium content than the commercially available sodium ibuprofen dosage form, and further provides an optimum hardness and low brittleness in equilibrium with excellent solubility. And high stability tablets/capsules, and which have the added advantage of an efficient cost manufacturing process.

It is an advantage of the present invention to provide a pharmaceutical composition comprising a sodium ibuprofen-containing core having a low sodium content (calculated based on the composition). The present invention provides a pharmaceutical composition in the form of a troche or caplet comprising further at least one coating wherein the ibuprofen obtained from a person taking the two cores has a _Tmax of about 40 minutes or less. The present invention provides a pharmaceutical composition wherein the core further comprises at least one binding agent. The present invention provides a pharmaceutical composition wherein the core sodium ibuprofen is present in the form of a dihydrate, and wherein the amount of the sodium ibuprofen dihydrate is 50% of the core weight of the pharmaceutical composition. 90% by weight. The present invention provides a pharmaceutical composition in the form of a coated tablet or coated caplet having a pH of from 6.0 to 8.0 in an aqueous solution of 40 mL of carbon dioxide-free water at 25 ° C. . The invention also provides a pharmaceutical composition further comprising one or more additional excipients in an amount of from 0.1 to 20% by weight based on the weight of the core of the pharmaceutical composition, and the one or more pharmaceutically acceptable binders and others The excipient is present in an amount of from 10 to 50% by weight based on the weight of the core of the pharmaceutical composition. The present invention provides a pharmaceutical composition having a hardness greater than 30 N and wherein the one or more pharmaceutically acceptable coatings comprise from 0.1 to 10% by weight based on the weight of the core of the pharmaceutical composition. The present invention provides a pharmaceutical composition which provides a total daily sodium content to a patient of less than 140 mg/day (including about 134 mg/day or less) and is provided in six doses per day based on a sodium content of 22.3 mg per dosage unit. For patients who need to be treated with sodium ibuprofen. The present invention provides a method of preparing a pharmaceutical composition comprising a sodium ibuprofen core having a low daily sodium content of less than 140 mg/day, wherein the T of ibuprofen obtained by two of the core persons is used _{The max} is about 40 minutes or less, which further includes the step of compressing the pharmaceutical composition into a core having a hardness greater than 30N. The present invention provides a pharmaceutically acceptable composition and a method for preparing the ibuprofen sodium core and corresponding coated tablets and caplets, which have high ibuprofen sodium core strength and hardness, relative to The commercially available sodium ibuprofen formulation has a low sodium content and further provides a sodium ibuprofen having excellent solubility properties and biological activity. The invention further provides a method of preparing a sodium ibuprofen composition. The method comprises combining sodium ibuprofen with a suitable excipient. In addition, a preferred method of preparing the tablets and caplets for the most efficient manufacture of large quantities of tablets and caplets is provided.

The invention and its advantages are further described in detail with the accompanying embodiments, examples, and drawings.

Table 1 shows the representative compositions and excipients of the drug of sodium ibuprofen in the formulation; Table 2 shows representative compositions and forms of the drug of sodium ibuprofen ingot containing lactose The function of the agent in the formulation; Figure 1 shows a representative flow chart for preparing 256.25 mg of sodium ibuprofen ingot; Table 3 summarizes the representative sodium ibuprofen formulation for preparing 256.25 mg of coated tablet Table 4 summarizes representative sodium ibuprofen formulations containing lactose for the preparation of 256.27 mg of coated lozenges; Table 5 summarizes the coating system for preparing coated ibuprofen ingots and caplets ; Table 6 summarizes the compression parameters of the roller press for the preparation of sodium ibuprofen core; Table 7 summarizes the compression data for the sodium ibuprofen tablet; Table 8 summarizes the compression data for the tablet of ibuprofen; Table 9 summarizes the Hardness data of sodium phenylpropionate coated tablets; Table 10 summarizes the hardness data of sodium ibuprofen coated tablets; Table 11 summarizes the statistics of sodium ibuprofen ingots in the process; Table 12 summarizes the differences in process Sodium styrene-butadiate ingot hardness data; Table 13 summarizes the hardness data of ibuprofen sodium capsules in the process; Table 14 summarizes the bulk brittleness data of a batch of lactose-containing ibuprofen sodium; Table 15 (a), 3(b) and 3(c) show representative compositions of sodium ibuprofen ingots; these formulations are used in the biological assays disclosed in Example 4; Table 16 summarizes the trials of sodium ibuprofen Data; Table 17 summarizes IBU pharmacokinetic parameters; Figure 2 shows the change in mean plasma concentration of ibuprofen from the biological test of Example 4 over time. Prototypes I-III correspond to Formulations I-III from Example 10, respectively (Tables 15(a)-15(c)); Figure 3 shows the mean plasma concentration of ibuprofen from the Bioassay of Example 4 (half Logarithmic scale) changes over time. Prototypes I-III correspond to formulations I-III from Example 10, respectively (Tables 15(a)-15(c)); Figure 4 shows the mean plasma concentration of ibuprofen from the biological test of Example 4. A two-hour change. Prototypes I-III correspond to formulations I-III from Example 10, respectively (Tables 15(a)-15(c)); Figure 5 summarizes the composition of many sodium ibuprofen at 25 ° C / 60% relative humidity Stability data under (RH); Figure 6 summarizes the stability of many sodium ibuprofen compositions at 25 ° C / 60% relative humidity (RH) and at 25 ° C / 60% relative humidity (RH) S Sexual data Figure 7 summarizes the stability data of many compositions of sodium ibuprofen at 30 ° C / 65% relative humidity (RH) and at 30 ° C / 60% relative humidity (RH) S; Figure 8 summarizes isobutylbenzene The dissolution data of the composition of sodium propionate at 30 ° C / 65% relative humidity (RH) and at 30 ° C / 65% relative humidity (RH) S; Figure 9 summarizes the composition of many sodium ibuprofen Dissolution data at 40 ° C / 75% relative humidity (RH) and at 30 ° C / 60% relative humidity (RH) U; Figure 10 summarizes the composition of many sodium ibuprofen at 40 ° C / 75% relative humidity (RH) and dissolution data at 40 ° C / 75% relative humidity (RH) S; Figure 11 summarizes the dissolution of many sodium ibuprofen compositions at 25 ° C / 60% relative humidity (RH) U Data; Figure 12 summarizes the dissolution data of many compositions of sodium ibuprofen at 25 ° C / 60% relative humidity (RH) and at 25 ° C / 60% relative humidity (RH) S; Figure 13 summarizes many different Dissolution data of a composition of sodium phenylpropionate at 30 ° C / 65% relative humidity (RH) and at 30 ° C / 60% relative humidity (RH) U; Figure 14 summarizes the composition of many sodium ibuprofen The number of dissolutions at 30 ° C / 65% relative humidity (RH) and at 30 ° C / 65% relative humidity (RH) S Figure 15 summarizes the dissolution data of many compositions of sodium ibuprofen at 40 ° C / 75% relative humidity (RH) and at 30 ° C / 60% relative humidity (RH) U; and Figure 16 summarizes many differences The dissolution data of the composition of sodium butyl propionate at 40 ° C / 75% relative humidity (RH) and at 40 ° C / 75% relative humidity (RH) S.

The present invention provides a sodium ibuprofen core and corresponding coated tablets and caplets formed by compression. The compositions and methods described herein produce tablets and caplets having advantageous characteristics, including rapid dissolution and excellent tablet strength. As used herein, the term "tablet" is intended to include lozenges, caplets, capsules, pills, or any other analog thereof. In addition, "tablet" means a small, substantially solid shaped pellet of any medical group. Compound. The shape of the tablet can be cylindrical, spherical, rectangular, capsular or random.

As used herein, the term "about" (or "about") means that the particular value may be within the range acceptable to those skilled in the art, depending on the nature of the value and its method of measurement.

Tablet strength is typically measured by a radial compression test (also known as a Brazilian test). See, for example, Pharmaceutical Dosage Forms: Tablets. 3rd Edition, Volume 1, edited by Larry Augsburger and Stephen Hoag, p. 606. When the tablet is broken in a specific manner, the result is evaluated as tensile strength. More generally, the maximum load at which a tablet breaks is referred to as crush strength or crushing force. The SI unit for this measurement is Newton (N), however Strong Cobb units (SCU) and Kilopons (Kp) are sometimes used. It is important to achieve a tablet of suitable strength to avoid breakage during processing after compression, during coating of the film, and during transport of the packaged product.

Tablets of the invention also include one or more water soluble excipients. Excipient is any component other than the active substance in the core or coating of sodium ibuprofen, and includes a binder, a diluent, a disintegrant, a flavoring agent, a coloring agent, a slip agent, a sour agent, and Sweetener.

For the purposes of this application, "binder" means one or more ingredients added to form granules and/or to enhance co-compaction during compression prior to or during granulation. The binding agent of the present invention comprises at least microcrystalline cellulose (MCC) and mannitol. MCC is a component of a three-dimensional matrix that is sheared in water to form millions of insoluble crystallites that form an extremely stable, thixotropic colloid. It has been proven to be a stable, safe and physiologically inert natural substance. Microcrystalline cellulose (MCC) is named for its unique compressibility and load carrying capacity in the ingot making process. When it is used as an excipient of a solid dosage form, it exhibits excellent characteristics. It is fully compacted under a wide range of compression pressures, has a high binding capacity and produces a tablet that is extremely hard, stable, but still rapidly disintegrable. Other advantages include low brittleness, inherent lubricity and the highest dilution potential of any binder. These properties make MCC particularly suitable for use as fillers and binders in the preparation of formulations by roller compaction, direct compression, and wet granulation. Mannitol, and preferably spray-dried D-mannitol having a medium particle size, An excellent diluent-binding agent with good compressibility. Cerium dioxide is also recognized for its binder characteristics and is used herein. One of ordinary skill will further appreciate that other binding agents can be added to formulate the compositions contemplated herein.

The lozenge may also comprise one or more of a slip agent material which improves the flow of the powder mixture and minimizes the change in weight of the lozenge. A slip agent such as cerium oxide can be used in the present invention. One of ordinary skill in the art will further appreciate that other slip agents can be added or used to formulate the compositions contemplated herein.

Further, the tablet of the present invention comprises a lubricant so that the finished tablet is discharged from the die after compression, and the tablet is prevented from sticking to the die face and bonding to each other. The two components included herein are MCC and sodium lauryl sulfate. In addition, the unique characteristic of sodium ibuprofen as one of the active ingredients is itself a good lubricant. One of ordinary skill in the art will further appreciate that other slip agents can be added or used to formulate the compositions contemplated herein.

As used herein, the term "disintegrant" refers to one or more substances that promote the disintegration of a pharmaceutical composition comprising a pharmaceutical formulation of the invention in water (or a fluid containing water in vivo). In certain embodiments, the disintegrant component comprises microcrystalline cellulose (MCC) and one or more crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, ion exchange resin, carboxyl Methylcellulose, hydroxypropylcellulose, calcium citrate, metal carbonate, sodium bicarbonate, calcium citrate or calcium phosphate. One of ordinary skill in the art will further appreciate that other disintegrants may be added or used to formulate the compositions contemplated herein.

Diluent is used broadly to refer to an inactive ingredient or filler that is added to a tablet or caplet in addition to the active drug. Mannitol and MCC, along with other features thereof, can be considered as diluents. One of ordinary skill in the art will appreciate that other diluents may be added or used to formulate the compositions contemplated herein.

In addition, and if desired, other materials commonly used in pharmaceutical formulations, such as perfumes (eg, caramel, strawberry, raspberry, cherry, milley) (magnasweet) 135, lime flavor, grape flavor, fruit extract and flavor enhancer (prosweet), flavor enhancer and sweetener (eg sucralose, aspartame, sodium saccharin, sorbitol, glucose, Sucrose), sour agents (such as citric acid), dyes or colorants. One of ordinary skill in the art will further appreciate that other flavoring agents may be added or used to formulate the compositions contemplated herein.

As used herein, "having a low sodium content" means a pharmaceutically acceptable composition that provides a maximum daily sodium content of less than 140 mg/day. 21 CFR 201.64 "Labeling Requirements for Over-the-Counter Drugs" states the subject of sodium content in OTC drugs. If the maximum daily dose includes more than 140 mg of sodium per day, a warning must be given. If the sodium content of the maximum daily dose indicated by the product is greater than 140 mg, the label of the OTC drug intended for oral administration should include the description under the heading "Warning" (or "Warning" if the warning is added)," If your diet has a [rough font] [plus special symbol] ¹ sodium limit, please consult a doctor before use." One of the advantages of the invention disclosed herein is that this warning is not required. The plan was to provide a total of 140 mg/day of sodium in multiple doses. For example, Example 2 discloses a lozenge comprising 256.27 mg of sodium ibuprofen. This is equal to the dose of 200 mg of ibuprofen. The single lozenge or caplet of Example 2 provided a sodium content of about 23 mg per dosage unit when an excipient containing only a small amount of sodium was used. With this lozenge, the individual can take six unit doses and still be below the maximum allowable daily dose of 1200 mg/day of OTC ibuprofen and below the 140 mg/day sodium threshold. In accordance with the present invention, it is contemplated that a small amount of additional sodium may be included in the compositions of the present invention, such as sodium lauryl sulfate (SLS) from Example 2. However, the compositions of the present invention still provide a total sodium content of less than 140 mg/day.

The pharmaceutical industry utilizes various methods to formulate pharmaceutical preparations into lozenge formulations. The preferred method for use in the compositions of the present invention disclosed herein is the compression of a roller press when preparing the ingredients for the ingot or subgroups of such ingredients. While having all the benefits, the granulation process provides, for example, improved material flow and content uniformity, but roller press compression can be used for wet granulation in terms of moisture, solvent Or heating (drying) sensitive compounds offer unique advantages. In the compression of the roller press, the powder is fed into two counter-rotating drums which attract the powder between the rollers by friction and compact the powder. Roller compression appears to be a simple process, but the basic mechanism is complicated by the large number of material properties and mechanical variables, such as material flow characteristics, friction with the drum surface, compressibility, compression plasticity, elastic properties, air. Permeability, drum surface, drum size, drum pressure, roll gap, drum speed, feed method and conditions (gravity or screw, screw design, vacuum or non-vacuum) and feed pressure. In fact, the development of rolling press compression formulations and methods still relies on experience, trial and error, and experimental design. Obviously, it is necessary to develop a method for the development and scale-up of the rolling press compression product process based on basic understanding but also practical application.

There are generally three controllable parameters in the press compression process: drum pressure, roll gap (or strip thickness can be controlled by feed screw speed when the band gap is not controlled) and drum speed. Because the consolidation of the solid mixture forming strip is the result of mechanical stress (vertical stress and shear stress) in the powder during compression of the roller, it is related to the vertical (compressive) stress and shear stress by detecting it. Sex to explore all the parameters.

Any method of forming the lozenge of the present invention into a desired shape while still maintaining its essential characteristics is encompassed within the scope of the present invention.

The lozenge composition can be mixed and milled by any method which results in the composition being substantially uniformly mixed during the preparation of the tablet composition.

Once the tablet composition is prepared, different shapes can be formed. In a preferred embodiment, the tablet composition is compressed into a shape. The method can include placing the tablet composition in a mold, applying pressure to the composition such that the shape of the composition is the surface shape of the mold in contact with the composition. The parameters that can be adjusted in the most commonly used tablet presses can have a greater impact on the ultimate strength and stability of the tablets contemplated by the present invention as disclosed herein. These parameters (including mold shape, pre-compression strength, compression force, turret speed) can be adjusted and affect the hardness and core defects of the tablet (including the primary particles constituting the core). Broken and sticky).

The advantage of the formulation of sodium ibuprofen compared to other formulations of sodium ibuprofen is that the use of sodium ibuprofen can form a sodium ibuprofen core with a low sodium content and further provide performance. Improved physical stability, high core hardness and high core strength, plus excellent solubility and bioavailability lozenges. Another advantage of the sodium ibuprofen composition of the present invention is that commercially available ibuprofen formulations comprise a poorly soluble active ingredient in acid form. Yet another advantage of the sodium ibuprofen cores and compositions of the present invention is the provision of coated lozenges/capsules having the requisite stability and solubility, including, for example, the desired _Tmax . The sodium ibuprofen composition of the present invention has an improved _Tmax in addition to other optimal parameters.

According to one embodiment, there is provided a pharmaceutical composition comprising a core comprising sodium ibuprofen, the composition having a low sodium content. The expression "tablet core" in the context of the present invention means a lozenge or caplet which does not contain a sugar coating or a film coating.

According to one embodiment, there is provided a pharmaceutical composition in the form of a lozenge or caplet further comprising at least one coating.

According to one embodiment, there is provided a pharmaceutical composition comprising a core comprising sodium ibuprofen, the ratio of sodium ibuprofen to total sodium content in the composition being about 11:1. The pharmaceutical composition further comprises a coated core comprising sodium ibuprofen, the coated core having a sodium content of less than 23 mg per dosage unit. Further provided is a pharmaceutical composition wherein the ibuprofen obtained from a person taking the two cores has a _Tmax of about 40 minutes or less.

According to an embodiment, a pharmaceutical composition is provided wherein the core further comprises at least one binding agent.

According to an embodiment, the composition comprises at least one binding agent. Examples of suitable binders are sugars (such as sucrose, glucose, fructose and lactose), hexoses (such as mannitol, xylitol, maltitol, sorbitol), hydrolyzed or enzymatically cleavage starches (such as maltodextrin), Cyclodextrins (such as P- and y-cyclodextrin) and compositions thereof.

According to one embodiment, the sodium ibuprofen ingot is present in the form of a dihydrate. The expression "sodium ibuprofen hydrate" in the context of the present invention includes all hydrates of sodium ibuprofen (including sodium ibuprofen dihydrate), sodium of racemic ibuprofen Salt and the sodium salt of the enantiomers S(+)-ibuprofen and R(-)-ibuprofen and the sodium salt of a mixture of such enantiomers. S(+)-Sodium ibuprofen hydrate and, in particular, racemic sodium ibuprofen hydrate are preferably used. According to an embodiment, the sodium ibuprofen hydrate is sodium ibuprofen dihydrate.

According to another embodiment, ibuprofen in the form of other salts may be added to the core of the invention and the corresponding compositions. Typical examples include, but are not limited to, calcium ibuprofen, potassium ibuprofen, lysine lysinate, ibuprofen sulphate, ibuprofen carbonate , phosphate, phosphate, hydrogen phosphate, oxide, hydroxide, citrate, tartrate, acetate or propionate, specifically basic sodium, trisodium citrate, disodium tartaric acid, tartaric acid Dipotassium, magnesium oxide, calcium oxide, magnesium hydroxide, calcium hydroxide, magnesium carbonate, calcium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, tricalcium phosphate, sodium acetate, potassium acetate , sodium propionate, etc., basic amino acids such as lysine and arginine, and combinations thereof.

According to one embodiment, a carbonate-free core having a pH of 6.0 to 8.0 and corresponding compositions are provided. The core and composition form a substantially supersaturated solution in an acidic medium that aids in rapid resorption. Compared with known ibuprofen drugs, the present invention can achieve effective blood levels and concentrations faster at the point of action, thereby accelerating the onset of analgesia and achieving the highest blood levels and concentrations at the point of action. . A large number of in vivo tests have confirmed that the use of conventional ibuprofen formulations requires a maximum blood content of about 1.5 hours after administration. In contrast, the tablet of the present invention containing no disintegrant achieves a maximum blood content after about 35 minutes. The lozenge of the present invention can therefore treat the pain particularly quickly and reduce the onset of analgesia and cause the patient to take another ingot The danger of the agent.

According to one embodiment, the ibuprofen sodium ingot comprises sodium ibuprofen dihydrate in an amount of from 50 to 99.9% by weight of the pharmaceutical composition.

According to one embodiment, the sodium ibuprofen ingot comprises sodium ibuprofen dihydrate in an amount of from 60 to 90% by weight based on the weight of the pharmaceutical composition.

According to an embodiment, the sodium ibuprofen ingot further comprises one or more additional excipients or fillers. The pharmaceutical composition is in the form of a coated tablet or coated caplet having an aqueous solution having a pH in the range of from 6.0 to 8.0.

According to one embodiment, the sodium ibuprofen tablet further comprises one or more pharmaceutically acceptable excipients in an amount of from 10 to 50% by weight of the pharmaceutical composition. Water soluble excipients are preferred. Examples of preferred suitable excipients are saccharides (such as sucrose, glucose, fructose and lactose), hexoses (mannitol, xylitol, maltitol, sorbitol), hydrolyzed or enzymatically cleavable starches (such as maltodextrin). ), cyclodextrin (such as P- and y-cyclodextrin), non-crosslinked (water-soluble) polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, polypropylene glycol, alkali metal salts, alkaline earth metal salts and An ammonium salt of an organic or inorganic acid, specifically sodium, potassium, magnesium and calcium salts (such as sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, potassium sulfate, magnesium sulfate, trimagnesium dicitrate, dicitric acid three) Calcium, calcium lactate, calcium gluconate, calcium hydrogen phosphate and the like). Particularly preferred excipients are hexoses (such as sorbitol and mannitol), non-crosslinked polyvinylpyrrolidone, maltodextrin and sodium chloride, in particular water-soluble, non-crosslinked polyvinylpyrrolidine Ketones, which are obviously also suitable for delaying the precipitation of ibuprofen in the stomach.

According to one embodiment, the pharmaceutical composition comprises a coating core having at least one coating comprising a sugar coating or a film coating wherein all of the conventional sugar coating and film coating materials are in principle suitable for use as a coating material. The thickness of the coating is not critical, however, in general, the coating ratio is only about 1 to 10% by weight, including about 3 to 6% by weight, based on the weight of the core of the tablet. Suitable examples of coating and coating materials can be found in the examples.

According to one embodiment, the ibuprofen sodium/capsule comprises a harder than 30N degree.

According to one embodiment, the sodium ibuprofen ingot/capsule comprises a hardness of greater than 40N.

According to an embodiment, the sodium ibuprofen ingot/capsule comprises a hardness greater than 80N.

According to one embodiment, the sodium ibuprofen ingot/capsule comprises a hardness greater than 90N.

The tablet may also be coated with a water soluble polymeric film that dissolves quickly. Membrane coatings include the uniform deposition of a typical polymeric film onto a substrate, typically by spray techniques. Advantages of the coated film coating method include minimizing the weight gain of the final dosage form, reducing processing time, and improving chip resistance. The coating composition contains a flavoring agent to mask the odor of the active ingredient, as needed. In addition, a polishing agent such as carnauba wax can be used as part of the coating process. One of ordinary skill will appreciate that other coating materials may be added or used to formulate the compositions contemplated herein. Further, methods other than the coating film coating method are also included herein.

Instance

Example 1

The following are examples of formulations contemplated by the inventors. Take 200mg of sodium ibuprofen ingot, which is a round, light brown film-coated tablet, printed in black ink, containing 256.25mg of sodium ibuprofen dihydrate per dosage unit (equivalent to 200mg dose difference) Butyric acid).

Table 1 summarizes the composition of a drug of sodium ibuprofen and the function of the excipients in the formulation.

Example 2

Another composition of a 200 mg dose of sodium ibuprofen coated caplets containing lactose and the function of the excipients in the formulation are summarized in Table 2. Take 200mg of sodium ibuprofen ingot, which is a round, light brown film-coated tablet, printed in black ink, containing 256.27mg of sodium ibuprofen dihydrate per dosage unit (equivalent to 200mg dose difference) Butyric acid).

Example 3

This example is a larger scale batch formulation contemplated by the inventors in accordance with Example 1. A batch of sodium ibuprofen ingot was prepared using a representative batch size of about 1.5 million tablets.

The preparation of sodium isobutyrolate consists of seven unit operations: weighing, mixing, roller compression/grinding, mixing, compression, coating/polishing, and printing. The components of each unit operation are weighed separately at the time of dispensing.

Each of the ibuprofen sodium premixes was prepared by mixing sodium ibuprofen dihydrate, mannitol, and colloidal cerium oxide and layering them into a box. Mix the contents of the box to a uniform. The mixture was then compacted by a roller press and ground into granules using a roller compactor equipped with a combined grinder. After the compression step of the roller press, microcrystalline cellulose, mannitol, colloidal cerium oxide, and sodium lauryl sulfate are sieved and added to the tank. Into the compressed mixture. The contents of the box were mixed until uniform. The compressed mixture was compressed into a tablet on a rotary tablet press. After the setting, the following tests were carried out in the process: average weight (421 to 439 mg, target 430 mg) and average hardness. The in-process test (average weight and average hardness) is carried out throughout the compression stage to ensure the quality of the tablet core produced. After compression, the core was coated with a sweetened film coat and a Carnauba Wax polishing layer was applied in a film coater.

a. Two boxes of materials are grouped together.

b. Ibuprofen sodium dihydrate should be divided into 50.0 kg aliquots (four parts).

c. Mannitol should be divided into three equal parts of 5.20 kg for the mannitol/colloidal ceria mixture.

d. Colloidal cerium oxide should be divided into three equal parts of 0.78 kg for the mannitol/colloidal cerium oxide mixture.

e. Mannitol should be divided into 12.0 kg three equal parts.

f. If the granulation yield (theoretical yield %) is outside the specified range (97.0-102.0%), the compressed mixture components should be calculated based on the actual yield.

g. An excess of the coating suspension was prepared to fill the priming of lines; the coating suspension was 20% solids.

h. Prepare a can of film coating solution for coating the batch (2 boxes).

i. Does not appear in the final dosage form and has been substantially removed during processing.

j. Distribute excess ink and alcohol for setting. The amount used includes an excess that may not be used during processing.

k. If necessary, use alcohol to dilute the ink.

Example 4

This example is a larger batch formulation contemplated by the inventors in accordance with Example 3. A batch of coated ibuprofen sodium ingot containing lactose is prepared using a representative batch size of about 679,000 tablets.

Example 5

Further examples of the preparation of coated ibuprofen sodium cores for lozenges and caplet products using the following coating systems are summarized in Table 5.

Example 6

Description of preparation method and process control

A flow chart for preparing 200 mg of sodium ibuprofen ingot is illustrated in Figure 1.

Example 7

The following preparation procedure illustrates the procedure for the preparation of a 200 mg sodium ibuprofen ingot.

Preparation

The following preparation procedure illustrates the steps of the preparation of a 200 mg pharmaceutical sodium ibuprofen ingot.

Weighing

The indicated amounts of each component are weighed out and placed in appropriately labeled containers.

Mixed (sodium ibuprofen premix)

The granulation mixture was mixed in a tank mixer. The batch consists of ten boxes. Charge the boxes according to the following procedure:

1) Preparation of a mixture of mannitol and colloidal cerium oxide.

2) Sift all ingredients into a suitable container via #20 mesh and separate all ingredients.

3) Alternately add aliquots of sodium isobutyrophenone dihydrate, mannitol, and mannitol/colloidal ceria mixture to the tank until all materials enter the tank.

The material was mixed for 3 to 15 minutes at 17 rpm ± 1 rpm. The mixing steps were repeated for each of the ten boxes.

Roller compression / grinding

The premix is fed directly from the box for mixing into the roller compactor. The roller press was held under the parameters listed in Table 6 to produce an acceptable strip.

After compression by the roller press, the strip was processed via a vibrating mill equipped with a 1.5 mm mesh screen. Collect the ground material into a suitable container.

Mixing (compressed mixing)

The compressed mixture was mixed in a tank mixer to make equal amounts of pellets per tank, respectively. Charge the boxes according to the following procedure:

1) Combine colloidal cerium oxide with microcrystalline cellulose using a suitable container.

2) The colloidal ceria/microcrystalline cellulose mixture, sodium lauryl sulfate, and mannitol were sieved through a #20 mesh screen.

3) The sieved colloidal ceria/microcrystalline cellulose mixture, sodium lauryl sulfate, and mannitol are added to the sodium ibuprofen for granulation contained in the tank.

The material was mixed for 9 to 18 minutes at 17 rpm ± 1 rpm.

This procedure is repeated from each batch of ten boxes.

compression

The compressed mixture is compacted into a core of the capsule using a rotary tablet press equipped with a circular or capsule mold. The average weight was measured to ensure content uniformity. Correct the deviation from the target weight by adjusting the fill depth. The average hardness is measured to ensure core performance and robustness. After passing through the dust collector and metal detector, the tablets are collected in a suitable storage container. Exemplary compression parameters for coated sodium ibuprofen ingots and caplets are summarized in Tables 7 and 8. It will be appreciated that a broader range of such compression parameters still applies to the present invention.

The compression and hardness data for representative ibuprofen sodium tablets and caplets are summarized in Tables 9-13.

a. The hardness is converted from scu to N and the thickness is converted from in to in mm.

Suspension preparation

1) Add the pigmented film material to the water and mix for at least 30 minutes.

2) Add the sweetener and one or more flavoring agents to the suspension and continue mixing for at least 15 minutes.

Membrane coat

1) Transfer a certain amount of caplet or lozenge core to a suitable size of the coated pan. A calculated amount of suspension is applied to the caplet or lozenge bed using the prepared coating system.

Once the application of the coating suspension is completed, Carnauba Wax is screened through a mesh screen to the caplet or lozenge bed.

2) Roll the caplets or lozenges to dispense Carnauba Wax.

3) Discharge the caplets or lozenges from the coater into a suitable container.

print

Print at a speed on the surface of the caplet or lozenge with a black ink (diluted with isopropanol if necessary) at a rate that produces acceptable print quality.

package

Packaging tablets or caplets by conventional techniques

Example 8

Brittleness data from the sodium ibuprofen coated lozenges of Example 1.

The stability and solubility test of the sodium ibuprofen composition is summarized in Figures 5-12.

Example 9

The brittleness data lines of the coating compositions from the coated ibuprofen sodium of Example 15(a) are summarized in Table 14. An exemplary volume fragility data for the bulk of sodium ibuprofen containing lactose is 0.47%. After specifying the number of rotations, the brittleness was tested according to the USP <1216> lozenge brittleness test.

Example 10

Preliminary test for comparing the absorption of sodium ibuprofen prototype lozenge

This preliminary test was conducted to evaluate the absorption curves of three different ibuprofen sodium prototype tablets compared to the current market for ibuprofen products (hereinafter referred to as "reference standards").

The purpose of this test is to compare the rate and extent of ibuprofen absorption in reference prototypes and sodium ibuprofen prototype tablets (up to 6 hours).

Overall test design and project description

This is a single-dose, randomized, open-label, inpatient, and four-way cross-combination trial. The plan enrolls in 16 healthy male and female individuals (the number of people is approximately equal) to ensure that at least 12 individuals complete the trial. The individuals were randomly assigned to 1 to 4 dosing sequences, and during each test period, a 400 mg dose of each ibuprofen formulation was received after one night of fasting. The interval between administrations during each trial was at least 48 hours. During each of the four trials, eighteen blood samples (3 mL each) were collected from each body in 6 hours to a heparin-containing tube for analysis of racemic ibuprofen. During the trial, approximately 216 mL of blood was drawn from each body (except for approximately 30 mL of blood required for safety and pregnancy assessment). Individuals were allowed to stay on site during the trial.

Test drug identity

Tables 15(a) through 15(c) describe prototypes I-III for use in biological experiments.

Table 15 (c): Formulation III Formulation III was made into a round brown tablet. The uncoated lozenge weighed 450 mg.

‧Treatment A: 2 x Ibuprofen sodium 256 mg prototype tablet formulation I (equal to 400 mg ibuprofen) at 0 hours; ‧ Treatment B: 2 x Ibuprofen at 0 hours Sodium 256mg prototype tablet formulation II (equal to 400mg ibuprofen); ‧ treatment C: 2 x ibuprofen sodium 256mg prototype tablet formulation III (equal to 400mg ibuprofen) at 0 hours ‧ Treatment D , reference: 2 x reference standard 200 mg (total dose = 400 mg) at 0 hours.

All treatments were administered under fasted conditions.

Treating

Biological analysis method

The racemic IBU in the plasma samples was analyzed by a validated assay using high performance liquid chromatography tandem mass spectrometry/mass spectrometry (HPLC MS/MS).

The following PK parameters are derived from: AUCL, C _max , Ln AUCL, Ln C _max , T _max , T _mec (time to 6.4 mcg/mL plasma concentration), T ₂₀ (time to ₂₀ mcg/mL plasma concentration), and T _Lag (the time between the start of administration and the start of absorption).

Pharmacokinetic comparison

Evaluate the following pairwise comparisons:

‧ Ibuprofen sodium prototype tablet formulation I (treatment A) versus reference standard (treatment D)

‧ Ibuprofen sodium prototype tablet formulation II (treatment B) versus reference standard (treatment D)

‧ Ibuprofen sodium prototype tablet formulation III (treatment C) versus reference standard (treatment D)

Statistical Analysis

Difference analysis (ANOVA) was used to analyze the association between AUCL and _Cmax data (calculated by logarithmic conversion and untranslated) and gender, individual (gender), time period, treatment and gender differences and treatment interactions between treatments. . If significant (at 0.10 level) is present, the gender difference and treatment interaction are retained in the final model. The individual (gender) is used as the error term and the gradual (type 1) squared sum is used to detect the gender effect.

A total of 17 individuals aged 23-44 years (8 (47%) males and 9 (53%) females) participated in the trial. The average age and body mass index of this population were 30.6 years (in the range of 23-44 years old) and 24.3 kg/m ² (in the range of 20.0-28.0 kg/m ² ). There were eleven (64.7%) system whites, followed by three (17.7%) blacks, two (11.8%) Asians, and one (4.9%) classified as "other" races. There are eight (47.1%) systems of Hispanic.

Pharmacokinetic results

Summary data for individual individual concentration data at each sampling time and plasma concentrations of ibuprofen at each sampling time are plotted below. The mean plasma concentration curve is illustrated in Figure 2 below (linear scale) and Figure 3 (half log ratio). The mean plasma concentration curve (linear ratio) up to 2 hours after administration was shown in FIG.

Pharmacokinetic data

The key results are summarized in Table 17 below. The three prototypes were equivalent to the reference standard organisms in terms of the degree of absorption of ibuprofen (AUCL) and the rate of absorption of ibuprofen ( _Cmax ) up to 6 hours, and the test formulations were formulated relative to the reference. The critical limits for each ratio of the material are included within the predetermined range (75.0-133.3%), and the bioequivalence is within the conventional range (80-125%). All three formulations were rapidly absorbed (Figure 4) and reached their respective maximum concentrations ( _Tmax ) on average over 40 minutes, faster than the relevant reference standard with an average _Tmax ~ 52 minutes. The three prototypes reached T _mec (time to 6.4 mcg/mL plasma concentration) within 12 minutes of administration and T ₂₀ (time to ₂₀ mcg/mL plasma concentration) within 18.2 minutes of administration, respectively, compared to their reference standards 22 minutes and 29 minutes faster.

In summary, the prototype II formulation exhibited the fastest PK curve for the relevant plasma concentration thresholds (T _max , T _mec and T ₂₀ ) and the highest C _max in the shortest time; however, the PK curves of the other two prototypes were also promising. And similar to prototype II.

The key results are summarized in Table 17 below.

^ Parameters based on the logarithm of the fitted logarithm.

Note: Each formulation contained a molar equivalent of 400 mg of ibuprofen.

Summary of overall pharmacokinetics

All three prototypes were bioequivalent to the reference standard in terms of the degree of absorption of ibuprofen (AUC) and the rate of absorption of ibuprofen ( _Cmax ) up to 6 hours. The critical limits of the ratios of the test formulations to the reference formulations are all included within the established range (80-125%) of bioequivalence. On average, all three prototypes were rapidly absorbed and their T _max values were within 40 minutes of administration.

Discussion and overall conclusion

This preliminary study compared the rate and extent of ibuprofen absorption by the three prototype ibuprofen sodium formulations with reference standards. In terms of AUCL and _Cmax , all three prototypes were determined to be bioequivalent to the reference standard, and all three prototypes were rapidly absorbed, with the maximum plasma concentration ( _Tmax ) being within 40 minutes of administration. In addition, the time to reach maximum plasma concentration (T _max ) for the three ibuprofen sodium prototypes, the time to reach the minimum effective plasma concentration (T _mec ), and the time to reach ₂₀ mcg/mL plasma concentration (T ₂₀ ) were more than the reference standard. Faster.

The absorption curve of another sodium ibuprofen product was compared with the reference standard, ibuprofen lysine and conventional ibuprofen, and it was found that these data were consistent with the earlier PK test, which confirmed In terms of _Cmax and AUC, sodium ibuprofen is bioequivalent to the reference standard and ibuprofen lysinate, but has a slightly faster _Tmax . In addition, this test found that in terms of AUC, sodium ibuprofen is bioequivalent to conventional ibuprofen but absorbs faster (higher _Cmax and faster _Tmax ). In this case, other formulations of sodium ibuprofen also provide faster onset of analgesia than standard ibuprofen tablets. These data show that the sodium ibuprofen ingots tested in this test are comparable to the standard. Ibuprofen tablets begin to cause analgesia faster, and at least as fast as the reference standard.

The three ibuprofen sodium prototype formulations and reference standards evaluated in this preliminary trial were well tolerated.

The scope of the invention is not limited by the specific embodiments described herein. In fact, it will be apparent to those skilled in the art that <RTIgt; These changes are still covered by the scope of the attached patent application.

It should be further understood that all values are approximate values and are provided for description.

Claims (5)

A pharmaceutical composition comprising a core comprising sodium ibuprofen dihydrate and a mixture of excipients comprising: (a) at least one selected from the group consisting of sucrose, glucose, fructose, lactose a binder of mannitol, xylitol, maltitol, sorbitol, hydrolyzed maltodextrin, cyclodextrin and combinations thereof, (b) at least one disintegrant comprising microcrystalline cellulose, and (c) At least one lubricant selected from the group consisting of stearic acid, microcrystalline cellulose, and combinations thereof, wherein each component of the excipient mixture is present in a functionally effective amount; wherein the excipient mixture comprises the core weight 10% to 50%; and wherein the pharmaceutical composition has a sodium content of less than 140 mg/1200 mg of free ibuprofen. The pharmaceutical composition of claim 1 in the form of a troche or caplet and further comprising at least one coat. The pharmaceutical composition of claim 1 or 2, wherein the core has a disintegration time of no more than 5.48 minutes; and wherein the batch of the core has a brittleness measurement of no greater than 0.55%. The pharmaceutical composition of claim 2 which has a hardness greater than 40N. The pharmaceutical composition of claim 3 which has a hardness of greater than 40N.